Asthma is a condition of the respiratory tract characterized by widespread, reversible narrowing of the airways (bronchoconstriction) and increased sensitivity (hyperresponsiveness) of the airways to a variety of stimuli. The familiar symptomology of asthma, i.e., coughing, wheezing, chest tightness, dyspnea, is caused by airway smooth muscle contraction, increased bronchial mucus secretion, and inflammation. Though seldom fatal, asthma has been estimated to affect 10-20% of school-aged children around the world, and hospital admissions for asthma in children have increased dramatically in recent years, one survey for the United States indicating that hospital admissions for children under 15 with asthma increased by at least 145% between 1970 and 1984. (See, M. R. Sears, 1990 1!.) Overall, it is estimated that 10 million Americans (4% of the population) have asthma, and some S4 billion is spent in treatment per year. (L. K. Altman, 1991 2!; C. Starr, 1991 3!.)
The causes of asthma are not completely understood, however the study of agents that trigger acute asthmatic episodes supports the theory that asthma is an immunological reaction by a subject in response to specific allergens of the subject's environment. These "triggers" exacerbate asthma by causing transient enhancement of airway hyperresponsiveness. Triggers that have been found to induce airway hyperresponsiveness include inhaled allergens, inhaled low molecular weight agents to which the subject has become sensitized (e.g., by occupational exposure), viral or mycoplasma respiratory infections, and oxidizing gases such as ozone and nitrogen dioxide. These "inducing" triggers can be distinguished from "inciting" triggers of bronchospastic episodes which include exercise, cold air, emotional stress, pharmacological triggers, inhaled irritants. The common feature of inducing triggers is that they are associated with airways inflammation; inciting triggers produce smooth muscle contractions (bronchospasms) which depend on the underlying degree of hyperresponsiveness, rather than increasing airways responsiveness themselves. (See, D. W. Cockcroft, 1990 4!.)
The recognition that airways inflammation is a cause of transient (acute) and also persistent airway hyperresponsiveness has had an impact on the treatment of asthma sufferers. Early treatments for asthma focused on bronchoconstriction and led to the development of many effective bronchodilator drugs. The most commonly prescribed were beta2-adrenoceptor agonists (epinephrine, isoproterenol, albuterol, salmeterol, etc.), xanthines (caffeine, theophylline, etc.) and cholinoceptor antagonists (atropine, acetylcholine, etc.). More recently, however, anti-inflammatory drugs have begun to replace bronchodilators as first-line treatments for asthma. Commonly prescribed anti-inflammatory agents for asthma include disodium cromoglycate (DSCG), nedocromil sodium, antihistamines such as ketotifen, and corticosteroids such as prednisolone. (See, F. M. C. Cuss, 1990 5! and P. M. O'Byrne, 1990 6!.)
The inflammatory response in asthma is typical for tissues covered by a mucosa and is characterized by vasodilation, plasma exudation, recruitment of inflammatory cells such as neutrophils, monocytes, macrophages, lymphocytes and eosinophils to the sites of inflammation, and release of inflammatory mediators by resident tissue cells (e.g., mast cells) or by migrating inflammatory cells. (J. C. Hogg, 1990 7!.) In allergen-induced asthma, sufferers often exhibit a dual response to exposure to an allergen--an "early phase" response beginning immediately after exposure and lasting until 1-2 hours after exposure, followed by a "late phase" response beginning about 3 hours after exposure and lasting sometimes until 8-10 hours or longer after exposure. (D. W. Cockroft, 1990 4!.) Late phase response in allergen-induced asthma and persistent hyperresponsiveness have been associated with the recruitment of leukocytes, and particularly eosinophils, to inflamed lung tissue. (W. M. Abraham et al., 1988 8!.) Eosinophils are known to release several inflammatory mediators, e.g., 15-HETE, leukotriene C.sub.4, PAF, cationic proteins, eosinophil peroxidase. (K. F. Chung, 1990 9!.)
Many of the drugs used to treat asthma have been found to block or neutralize the effects of the release of inflammatory mediators which regulate the inflammatory response. For example, beta2-adrenoceptor agonists and DSCG are potent stabilizers of mast cells, which are capable of releasing many mediators, including histamine, prostaglandins, leukotrienes, platelet activating factor (PAF), and chemotactic factors for neutrophils and eosinophils; corticosteroids, as another example, complex with steroid hormone receptors, which leads to the synthesis of proteins, such as lipocortins, that produce anti-inflammatory effects. (F. M. C. Cuss, 1990 5!.)
Although known asthma medications have some effect on leukocyte recruitment into the lung (W. M. Abraham et al., 1990 8!), none of these drugs is effective to directly block migration of leukocytes into inflamed tissues.
Inflammatory leukocytes are recruited to sites of inflammation by cell adhesion molecules that are expressed on the surface of endothelial cells and which act as receptors for leukocyte surface proteins or protein complexes. Eosinophils have recently been found to participate in three distinct cell adhesion pathways to vascular endothelium, binding to cells expressing intercellular adhesion molecule-1 (ICAM-1), endothelial cell adhesion molecule-1 (ELAM-1), and vascular cell adhesion molecule-1 (YCAM-1). (P. F. Weller et al., 1991 10!; G. M. Walsh et al., 1991 11!; B. S. Bochner et al., 1991 12!; and A. Dobrina et al., 1991 13!.) VCAM1 binds to the .alpha..sub.4 .beta..sub.1, integrin, VLA-4, which is expressed on various lymphoid cells, including eosinophils (Weller et al., 1991 10!; Elices et al. 1990 14!). That eosinophils express VLA-4 differentiates them from other inflammatory cells such as neutrophils, which bind to ELAM-1 and ICAM-1 but not VCAM-1.
The VLA-4-mediated adhesion pathway was investigated in an asthma model to examine the possible role of VLA-4 in leukocyte recruitment to inflamed lung tissue. It has now been discovered that administering anti-VLA-4 antibody inhibits both the late phase response and airway hyperresponsiveness in allergic sheep. Surprisingly, administration of anti-VLA-4 led to a reduction in the number of both neutrophils and eosinophils in the lung at 4 hours after allergen challenge, even though both cells have alternate adhesion pathways by which they can be recruited to lung tissues. Also surprisingly, inhibition of hyperresponsiveness in the treated sheep was observed which continued to 1 week, even though infiltration of leukocytes, including neutrophils and eosinophils, was not significantly reduced over time.